Recently, several investigators have explored the use of 17O for magnetic resonance (NMR) imaging of the cerebral metabolic rate of oxygen consumption (CMRO2). For example, see Arai et al. in “Cerebral oxygen utilization analyzed by the use of oxygen-17 and its nuclear magnetic resonance,” Biochem. Biophys. Res. Commun. 169: 153-8, 1990; Fiat et al. in “17O magnetic resonance imaging of the human brain,” Neurol. Res. 26: 803-8, 2004; Hopkins et al. in “Improved sensitivity of proton MR to oxygen-17 as a contrast agent using fast imaging: detection in brain,” Magn. Res. Med. 7: 222-9, 1988; Ogawa et al. in “Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields,” Magn. Res. Med. 14: 68-78, 1990; Pekar et al. in “In vivo measurement of cerebral oxygen consumption and blood flow using 17O magnetic resonance imaging,” Magn. Res. Med. 21: 313-9, 1991; Reddy et al. in “Detection of 17O by proton T1 rho dispersion imaging,” J. Magn. Reson. Series B 108: 276-9, 1995; and Zhu et al. in “In vivo 17O NMR approaches for brain study at high field. NMR,” Biomed. 18: 83-103, 2005. Of the three naturally occurring isotopes of oxygen, only 17O, a stable non-toxic isotope, is NMR active. This nucleus has a 0.037% natural abundance, is relatively NMR insensitive, and has short relaxation times due to the quadrupolar interactions of the spin 5/2 nucleus. Gaseous 17O2, whether dissolved in plasma or tissue, or bound to hemoglobin, is invisible to NMR detection. The H217O that is produced from 17O2 metabolism, however, is detectable by NMR and can be measured either directly around the 17O Larmor frequency, or with greater sensitivity by measuring the changes in T2 or T1ρ weighted proton NMR signal caused by 17O—1H scalar coupling and proton chemical exchange. In contrast to other methods for imaging CMRO2, therefore, 17O approaches can detect metabolically generated labeled water without any contributions to the signal from labeled molecular oxygen.
The simplest way to deliver 17O2 gas is by inhalation, as reported previously by Arai et al. in “In vivo oxygen-17 nuclear magnetic resonance for the estimation of cerebral blood flow and oxygen consumption,” Biochem. Biophys. Res. Commun. 179: 954-61, 1991; Fiat et al. in “Determination of the rate of cerebral oxygen consumption and regional cerebral blood flow by non-invasive 17O in vivo NMR spectroscopy and magnetic resonance imaging. Part 2. Determination of CMRO2 for the rat by 17O NMR, and CMRO2, rCBF and the partition coefficient for the cat by 17O MRI,” Neurol. Res. 15: 7-22, 1993; Fiat et al. in “Determination of the rate of cerebral oxygen consumption and regional cerebral blood flow by non-invasive 17O in vivo NMR spectroscopy and magnetic resonance imaging: Part 1. Theory and data analysis methods,” Neurol. Res. 14: 303-11, 1992; Tailor et al. in “Proton MRI of metabolically produced H2 17O using an efficient 17O2 delivery system,” Neuroimage 22: 611-8, 2004; Zhang et al. in “Simplified methods for calculating cerebral metabolic rate of oxygen based on 17O magnetic resonance spectroscopic imaging measurement during a short 17O2 inhalation,” J. Cereb. Blood Flow Metab. 24: 840-8, 2004; and Zhu et al. in “Development of (17)O NMR approach for fast imaging of cerebral metabolic rate of oxygen in rat brain at high field,” Proc. Natl. Acad. Sci. USA 99: 13194-9, 2002. For quantitative measurement of CMRO2, gas mixtures enriched with 17O2 have been administered typically as a pulse over a time period ranging from 2 minutes to 40 minutes. During this period of inhaling gas enriched in 17O2, the 17O is delivered to all tissues and metabolized in the mitochondria to produce H217O. The change in local MRI signal is directly proportional to the amount of labeled water, and the rate of H217O production is in turn directly related to oxygen metabolism in the region of interest. The H217O, however, does not just accumulate at the site of its production in the mitochondria, but also diffuses out of the local tissue to the venous circulation. Additionally, H217O produced in tissues outside of the region of interest (ROI) diffuse to their local venous circulations, and are then convectively transported to arterial blood. This H217O produced in other tissues enters the ROI in the arterial circulation, and also diffuses into tissue in the local ROI. The resulting signal is therefore a complex combination of the water production from the local CMRO2 of interest, along with water migration into and out of the tissue. Interpreting the MRI signal in terms of local CMRO2 specifically, therefore, can be difficult.
The present invention is directed to an alternative approach that delivers the 17O2 in a very brief pulse, on the order of 1 minute or less. Owing to time lags for both convection and diffusion, H217O produced outside of the ROI should not have time to enter the ROI before local production of H217O has commenced. During a short enough delivery interval, therefore, the regional signal should be much simpler to interpret, primarily determined by water formed locally from the 17O2. However, systems for mechanical ventilation are not usually designed to make a sharp step change in gas concentration, for example the pulse of 17O2 desired in the CMRO2 application. Additionally, ventilator circuits are not usually provided with a way to selectively recover parts of exhaled gas, which is enriched with very expensive 17O2 during the pulsed administration. The present invention is directed to these needs in the art.